Purpose. Multiple myeloma remains a fatal hematologic malignancy, affecting over 70,000 people in the US. The in vivo study of the initial cellular and molecular events resulting in myeloma is severely limited in patients with myeloma. The 5T Radl murine model of myeloma allows the study of myeloma establishment in addition to disease progression. One of the important features of the 5T Radl model is that the myeloma cells will only grow in the syngeneic KaLwRij mice, and not in closely related C57Bl6 mice, suggesting an important role of the host microenvironment in the initial stages of myeloma development. In support of this, our preliminary studies have demonstrated that a bone marrow stromal cell (BMSC) line, isolated from myeloma-bearing KaLwRij mice can promote the development of myeloma in non-permissive C57Bl6 mice, thus enabling, for the first time, myeloma development in a non-permissive microenvironment in vivo. Further studies, including microarray analysis, have determined that both the KaLwRij bone marrow microenvironment and the myeloma-promoting BMSCs are distinct from their normal counterparts in a number of ways, the most significant of which was a decrease in expression of adiponectin. Taken together, these in vivo studies suggest that unique changes in the host BM microenvironment play a critical role in the development of multiple myeloma in vivo and strongly implicate bone-marrow derived adiponectin in the initial establishment of myeloma. Hypothesis. The overall hypothesis is that changes in the host BM microenvironment, including specific changes in BMSCs and a decrease in adiponectin, create a permissive microenvironment for the establishment and progression of myeloma. Research Design. To evaluate this hypothesis we will utilize the well-characterized 5T RADL model of myeloma. We propose the following specific aims. (i) To determine the cellular interactions by which specific BMSCs promote myeloma, using in vitro and in vivo cocultures of myeloma cells, 14M1 BMSCs and primary BMSCs from myeloma-bearing mice, (ii) to determine the role of bone marrow-derived adiponectin in multiple myeloma in vivo, using bone marrow transplants from adiponectin-deficient mice and over-expression of adiponectin to investigate the specific role of bone-marrow derived adiponectin in myeloma pathogenesis in vivo. We will also investigate the expression and function of adiponectin and its receptors in patients with multiple myeloma, (iii) to determine the therapeutic potential of increasing adiponectin in vivo on myeloma bone disease, using an apolipoprotein mimetic peptide, L-4F which is known to increase serum adiponectin concentrations in vivo. We will treat myeloma-bearing mice with L-4F in vivo. Outcomes. The proposed studies will elucidate essential cellular and molecular mechanisms in the initial establishment and progression of myeloma, and identify novel therapeutic approaches for the treatment of this fatal malignancy. PUBLIC HEALTH RELEVANCE: Multiple myeloma is a fatal hematologic malignancy. Our data demonstrates that specific changes in the cells of the bone marrow microenvironment are responsible for the initial establishment and progression of myeloma. The proposed studies will investigate these changes and therefore identify novel therapeutic targets and new approaches for the prevention and treatment of myeloma.